The present invention relates to cyclopropylindole derivatives and pharmaceutical compositions comprising said derivatives useful for the treatment of various psychiatric disorders and premature ejaculation.
Selective serotonin reuptake inhibitors (SSRIs) are effective for the treatment of mental depression and have been reported to be useful for treating chronic pain. See R. W. Fuller, Pharmacologic Modification of Serotonergic Function: Drugs for the Study and Treatment of Psychiatric and Other Disorders,xe2x80x9d J. Clin. Psychiatry, 47:4 (Suppl.) April 1986, pp. 4-8 and Selective Serotonin Reuptake Inhibitors, edited by J P Feighner and W F Boyer, Chichester, England. John Wiley and Sons, 1991, pp. 89-108. SSRI""s have also demonstrated efficacy for the treatment of anxiety disorders. More recently, SSRI""s have demonstrated efficacy in the treatment of premature ejaculation. See Kim and Paick, Short-term Analysis of the Effects of As Needed Use of Sertraline at 5 pm for the Treatment of Premature Ejaculation, Urology 54:544-547 (1999); McMahon and Touma, Treatment of Premature Ejaculation with Paroxetine Hydrochloride As Needed: 2 Single-Blind Placebo Controlled Crossover Studies Journal of Urology 161:1826-1830 (1999); Haensal et al., Clomipramine and sexual function in men with premature ejaculation and controls Journal of Urology 156:1310-1315 (1996); and McMahon and Touma, Treatment of Premature Ejaculation with Paraoxetine Hydrochloride International Journal Impotence Research 11:241-246 (1999). Thus novel SSRI""s effective for the treatment of these and other disorders would be greatly advantageous.
Thus according to a first embodiment of a first aspect of the present invention are provided compounds of Formula (I) 
and pharmaceutically acceptable salts or solvates thereof
wherein
A1 and A2 are each independently C1-4alkylene or a bond;
A3 is C1-4alkylene or C1-4alkylidene;
A4 is C1-4alkylene or a bond and is attached to X, X1 or X2;
X, X1, X2 and X3 are independently C or CH;
J is C1-4alkyl;
p is 0 or 1;
R1 and R2 are independently H, C1-3alkyl, C3-6cycloalkyl, phenyl, xe2x80x94O-phenyl, xe2x80x94N(H)C(O)Oxe2x80x94C1-4alkyl or C1-4alkyl-N(H)C(O)Oxe2x80x94;
said C3-6cycloalkyl, phenyl or O-phenyl being independently and optionally substituted with C1-4alkyl, C1-3alkoxy or halo;
or are independently selected from the group of heterocyclic moieties consisting of thienyl, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl, morpholino, adamantyl, indolyl, isoindolyl, indolinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl and tetrahydroisoquinolinyl, wherein said heterocyclic moieties are optionally substituted with halo, C1-4alkyl, C1-4alkoxy or cyano;
or wherein xe2x80x94A1xe2x80x94R1 and xe2x80x94A2xe2x80x94R2 together with the nitrogen to which they are attached form pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl, morpholino, adamantyl, indolyl, isoindolyl, indolinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl or tetrahydroisoquinolinyl and are optionally substituted with halo, C1-4alkyl, C1-4alkoxy, cyano or benzyl;
R3 is H or C1-4alkyl;
m is 0 or 1;
R4 and R5 are independently hydrogen, cyano, halo, nitro or C1-3perfluoroalkyl;
wherein said R4 or R5 may be independently attached to X, X1, X2 or X3;
n is 0 or 1;
G is N, O or S;
G1 is N or CH;
Y is (D)H wherein D is C; and
Z is (E)H wherein E is C;
provided that
both R4 and R5 are not attached to the same of said X, X1, X2 or X3;
if G is O or S, then m is 0;
if G is N, then m is 1;
if R1 is xe2x80x94N(H)C(O)OC1-4alkyl, C1-4alkyl-N(H)C(O)Oxe2x80x94 or said heterocyclic moiety wherein said heterocyclic moiety contains a nitrogen atom and said nitrogen atom is attached to A1, then A1 is C2-4alkylene;
if R2 is xe2x80x94N(H)C(O)OC1-4alkyl, C1-4alkyl-N(H)C(O)Oxe2x80x94 or said heterocyclic moiety wherein said heterocyclic moiety contains a nitrogen atom and said nitrogen atom is attached to A2, then A2 is C2-4alkylene;
if R1 is N(H)C(O)Oxe2x80x94C1-4alkyl, C1-4alkylxe2x80x94N(H)C(O)Oxe2x80x94 or a heterocyclic moiety selected from the group consisting of thienyl, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl, morpholino, adamantyl, indolyl, isoindolyl, indolinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl and tetrahydroisoquinolinyl, wherein said heterocyclic moieties are optionally substituted with halo, C1-4alkyl, C1-4alkoxy or cyano, then R2 is H or C1-3alkyl;
if R2 is xe2x80x94N(H)C(O)Oxe2x80x94C1-4alkyl, C1-4alkyl-N(H)C(O)Oxe2x80x94 or a heterocyclic moiety selected from the group consisting of thienyl, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl, morpholino, adamantyl, indolyl, isoindolyl, indolinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl and tetrahydroisoquinolinyl, wherein said heterocyclic moieties are optionally substituted with halo, C1-4alkyl, C1-4alkoxy or cyano, then R1 is H or C1-3alkyl;
if A4, R4 or R5 are attached to X, then X is C;
if A4, R4 or R5 are attached to X1, then X1 is C;
if A4, R4 or R5 are attached to X2, then X2 is C;
if R4 or R5 are attached to X3, then X3 is C;
if R4 is F and is attached to X and if A3 is methylene, then xe2x80x94A1xe2x80x94R1 and xe2x80x94A2xe2x80x94R2 together with the nitrogen to which they are attached is not N-methyl-piperazinyl; and
if R4 is F and is attached to X and if A3 is methylene, then xe2x80x94A1xe2x80x94R1 and xe2x80x94A2xe2x80x94R2 together with the nitrogen to which they are attached is not tetrahydroquinolinyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein p is 0.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein G is N and G1 is CH.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein G is S and G1 is CH.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein G is N and G1 is N.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein G is S and G1 is N.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein G is O and G1 is N.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 is methyl and R2 is methyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A1 is a bond, R1 is methyl, A2 is a bond and R2 is methyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R3 is H and m is 1.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R4 and R5 are halo.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R4 is hydrogen.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R4 is fluoro.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R4 is cyano.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R4 and R5 are each fluoro.
According to another embodiment of the first aspect of the present invention are compounds of Formula (I) wherein D in relation to the four moieties to which it is attached has an absolute configuration of S; E in relation to the four moieties to which it is attached has an absolute configuration of S; and wherein the hydrogen atom attached to D is in the trans configuration to the hydrogen atom attached to E.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A3 is C1-4alkylene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A3 is C1-4alkylidene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A3 is methylene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A4 is a bond.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A4 is methylene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A4 is attached X1.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A4 is attached X.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R4 is attached X.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A1 is a bond, A2 is a bond, R1 is methyl and R2 is methyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 is independently selected from the group of heterocyclic moieties consisting of thienyl, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl, morpholino, adamantyl, indolyl, isoindolyl, indolinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl and tetrahydroisoquinolinyl, wherein said heterocyclic moieties are optionally substituted with halo, C1-4alkyl, C1-4alkoxy or cyano; A1 is C1-4alkylene; R2 is H or C1-3alkylene; and A2 is a bond.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 is independently selected from the group of heterocyclic moieties consisting of thienyl, imidazolyl, pyridyl, piperidinyl, piperazinyl, morpholino, adamantyl, indolyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl; A1 is C1-4alkylene; R2 is H or C1-3alkylene; and A2 is a bond.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R2 is independently selected from the group of heterocyclic moieties consisting of thienyl, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl, morpholino, adamantyl, indolyl, isoindolyl, indolinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl and tetrahydroisoquinolinyl, wherein said heterocyclic moieties are optionally substituted with halo, C1-4alkyl, C1-4alkoxy or cyano; A2 is C1-4alkylene; R1 is H or C1-3alkylene; and A1 is a bond.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R2 is independently selected from the group of heterocyclic moieties consisting of thienyl, imidazolyl, pyridyl, piperidinyl, piperazinyl, morpholino, adamantyl, indolyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl; A2 is C1-4alkylene; R1 is H or C1-3alkylene; and A1 is a bond.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 and R2 are independently H, C1-3alkyl, C3-6cycloalkyl, phenyl, xe2x80x94O-phenyl, or xe2x80x94N(H)C(O)Oxe2x80x94C1-4alkyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 and R2 are independently H, C1-3alkyl, or xe2x80x94N(H)C(O)Oxe2x80x94C1-4alkyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 and R2 are independently H, C1-3alkyl, C3-6cycloalkyl, phenyl, or xe2x80x94O-phenyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 and R2 are independently H, C1-3alkyl, or are independently selected from the group of heterocyclic moieties consisting of thienyl, imidazolyl, pyridyl, piperidinyl, piperazinyl, morpholino, adamantyl, indolyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R2 is H or C1-3alkyl and R1 is C3-6cycloalkyl, phenyl, xe2x80x94O-phenyl, or xe2x80x94N(H)C(O)Oxe2x80x94C1-4alkyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R2 is H or C1-3alkyl and R1 is N(H)C(O)Oxe2x80x94C1-4alkyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R2 is H or C1-3alkyl and R1 is C3-6cycloalkyl, phenyl or xe2x80x94O-phenyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R2 is H or C1-3alkyl and R1 is selected from the group of heterocyclic moieties consisting of thienyl, imidazolyl, pyridyl, piperidinyl, piperazinyl, morpholino, adamantyl, indolyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 is H or C1-3alkyl and R2 is C3-6cycloalkyl, phenyl, xe2x80x94O-phenyl, or xe2x80x94N(H)C(O)Oxe2x80x94C1-4alkyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 is H or C1-3alkyl and R2 is N(H)C(O)Oxe2x80x94C1-4alkyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 is H or C1-3alkyl and R2 is C3-6cycloalkyl, phenyl or xe2x80x94O-phenyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 is H or C1-3alkyl and R2 is selected from the group of heterocyclic moieties consisting of thienyl, imidazolyl, pyridyl, piperidinyl, piperazinyl, morpholino, adamantyl, indolyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein xe2x80x94A1xe2x80x94R1 and xe2x80x94A2xe2x80x94R2 together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl, morpholino, adamantyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl and are optionally substituted with benzyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein
A1 and A2 are each independently C1-4alkylene or a bond;
A3 is C1-4alkylene;
A4 is a bond and is attached to X or X1;
R1 and R2 are independently H, C1-3alkyl, C3-6cycloalkyl, phenyl, xe2x80x94O-phenyl or xe2x80x94N(H)C(O)Oxe2x80x94C1-4alkyl;
said C3-6cycloalkyl, phenyl or O-phenyl being independently and optionally substituted with C1-4alkyl, C1-3alkoxy or halo;
or are independently selected from the group of heterocyclic moieties consisting of thienyl, imidazolyl, pyridyl, piperidinyl, piperazinyl, morpholino, adamantyl, indolyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl;
or wherein xe2x80x94A1xe2x80x94R1 and xe2x80x94A2xe2x80x94R2 together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl, morpholino, adamantyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl and are optionally substituted with benzyl;
R3 is H or C1-4alkyl;
m is 0 or 1;
R4 is cyano or halo and is attached to X or X1;
n is 0;
X and X1 are each C;
X2 and X3 are each CH;
G is N, O or S;
G1 is N or CH;
Y is (D)H wherein D is C; and
Z is (E)H wherein E is C;
provided that
if G is O or S; then m is 0;
if G is N, then m is 1;
if R1 is xe2x80x94N(H)C(O)OC1-4alkyl or said heterocyclic moiety wherein said heterocyclic moiety contains a nitrogen atom and said nitrogen atom is attached to A1, then A1 is C2-4alkylene;
if R2 is xe2x80x94N(H)C(O)OC1-4alkyl or said heterocyclic moiety wherein said heterocyclic moiety contains a nitrogen atom and said nitrogen atom is attached to A2, then A2 is C2-4alkylene;
if R1 is xe2x80x94N(H)C(O)Oxe2x80x94C1-4alkyl or said heterocyclic moiety, then R2 is H or C1-3alkyl;
if R2 is xe2x80x94N(H)C(O)Oxe2x80x94C1-4alkyl or said heterocyclic moiety, then R1 is H or C1-3alkyl;
if R4 is F and is attached to X and if A3 is methylene, then xe2x80x94A1xe2x80x94R1 and xe2x80x94A2xe2x80x94R2 together with the nitrogen to which they are attached is not N-methyl-piperazinyl; and
if R4 is F and is attached to X and if A3 is methylene, then xe2x80x94A1xe2x80x94R1 and xe2x80x94A2xe2x80x94R2 together with the nitrogen to which they are attached is not tetrahydroquinolinyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein said compounds exhibit greater SERT binding than hD2L binding as described herein.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein said compounds exhibit less SERT binding than hD2L binding as described herein.
According to various embodiments of a second aspect of the present invention are provided pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein.
The compounds of the present invention may be useful in the treatment or prevention of disorders in which the regulation of monoamide transporter function is implicated. Disease states that may be implicated include hypertension, depression (e.g., depression in cancer patients, depression in Parkinson""s patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, paediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, and post partum depression), generalized anxiety disorder, phobias (e.g., agoraphobia, social phobia and simple phobias), posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, eating disorders (e.g., anorexia nervosa and bulimia nervosa), obesity, chemical dependencies (e.g., addictions to alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepines), cluster headache, migraine, pain, Alzheimer""s disease, obsessive-compulsive disorder, panic disorder, memory disorders (e.g., dementia, amnestic disorders, and age-related cognitive decline (ARCD)), Parkinson""s diseases (e.g., dementia in Parkinson""s disease, neuroleptic-induced parkinsonism and tardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion), negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette""s syndrome, trichotillomania, kleptomania, male impotence, attention deficit hyperactivity disorder (ADHD), chronic paroxysmal hemicrania, headache (associated with vascular disorders), emotional lability, pathological crying and sleeping disorder (cataplexy).
Disorders of particular interest include depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, substance abuse disorders and sexual dysfunction including (in particular) premature ejaculation. The compounds of the present invention may be administered alone or as part of a combination therapy.
Premature ejaculation may be defined as persistent or recurrent ejaculation before, upon or shortly after penile penetration of a sexual partner. It may also be defined as ejaculation occurring before the individual wishes [see The Merck Manual, 16th edition, p. 1576, published by Merck Research Laboratories, 1992].
Thus according to various embodiments of a third aspect of the present invention are provided methods of treating conditions selected from the group consisting of depression, anxiety disorders, premature ejaculation, urinary incontinence, chronic pain, obsessive-compulsive disorder, feeding disorders, premenstrual dysphoric disorder, hot flashes, panic disorders, posttraumatic stress disorder and social phobia comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein.
According to various embodiments of a fourth aspect of the present invention are provided methods of treating psychotic disorders including bipolar disorder and schizophrenia comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) exhibiting greater than or equal hD2L binding than SERT binding as defined herein.
According to various embodiments of a fifth aspect of the present invention are provided methods of enhancing the treatment of conditions selected from the group consisting of depression, anxiety disorders, premature ejaculation, urinary incontinence, chronic pain, obsessive-compulsive disorder, feeding disorders, premenstrual dysphoric disorder, panic disorders, posttraumatic stress disorder and social phobia comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) having SERT binding as defined herein and a pharmaceutically acceptable formulation of agents selected from the group consisting of (Lithium, 5-hydroxytryptophan, or a 5-HT1B/1D antagonist such as (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]-4-morpholino-benzamide.
According to a first embodiment of a sixth aspect of the present invention are provided methods of treating refractory depression comprising the administration to a human in need thereof an effective amount of a pharmaceutically acceptable formulation comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation containing a reversible and selective MAO-A inhibitor.
According to another embodiment of the sixth aspect of the present invention are provided methods of treating refractory depression comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation containng one or more reversible and selective MAO-A inhibitors selected from the group consisting of moclobemide, brofaromine and befloxatone.
According to another embodiment of the sixth aspect of the present invention are provided methods of treating refractory depression comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulation comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation containing a 5-HT1A antagonist.
According to another embodiment of the sixth aspect of the present invention are provided methods of treating refractory depression comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation containing a 5-HT1A antagonist selected from the group consisting of pindolol and WAY-100,635.
According to another embodiment of the sixth aspect of the present invention are provided methods of treating refractory depression comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation containng a 5-HT1B antagonist.
According to another embodiment of the sixth aspect of the present invention are provided methods of treating refractory depression comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation containing a partial 5-HT1A/1B antagonist.
According to another embodiment of the sixth aspect of the present invention are provided methods of treating refractory depression comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation containing buspirone.
According to another embodiment of the sixth aspect of the present invention are provided methods of treating refractory depression comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation containing methylphenidate.
According to a seventh aspect of the present invention are provided methods of treating obsessive compulsive disorder comprising the administration to an adolescent or child in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation containng clomipramine.
According to a first embodiment of an eighth aspect of the present invention are provided methods of treating refractory psychotic depression comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation of an antipsychotic agent.
According to another embodiment of the eighth aspect of the present invention are provided methods of treating refractory psychotic depression comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation of an antipsychotic agent selected from the group consisting of aripiprazole, olanzapine, risperdal, clozapine, ziprasidone, haldol, thiothixene and quetiapine fumarate.
According to a ninth aspect of the present invention are provided methods of treating exogenous obesity comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation of phentermine.
According to a first embodiment of a tenth aspect of the present invention are provided methods of treating disorders or conditions which can be facilitated by altering circadian rhythms comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation of a nitric oxide sythase inhibitor.
According to another embodiment of the tenth aspect of the present invention are provided methods of treating disorders or conditions which can be facilitated by altering circadian rhythms comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation of a selective neuronal nitric oxide sythase inhibitor.
According to another embodiment of the tenth aspect of the present invention are provided methods of treating disorders or conditions which can be facilitated by altering circadian rhythms comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation of a nitric oxide sythase inhibitor said conditions selected from the group consisting of blindness, obesity, seasonal affective disorder, bipolar disorder, jet lag, circadian sleep rhythms disorder, sleep deprivation, parasomnias, REM sleep disorders, hypersomnia, sleep-wake cycle disorders, narcolepsy and sleep disorders associated with shift work or irregular work schedules, nocturnal enuresis and restless-legs syndrome.
According to another embodiment of the tenth aspect of the present invention are provided methods of treating disorders or conditions which can be facilitated by altering circadian rhythms comprising the administration to a human in need thereof an effective amount of pharmaceutically acceptable formulations comprising compounds of Formula (I) as defined herein and a pharmaceutically acceptable formulation of a selective neuronal nitric oxide sythase inhibitor said conditions selected from the group consisting of blindness, obesity, seasonal affective disorder, bipolar disorder, jet lag, circadian sleep rhythms disorder, sleep deprivation, parasomnias, REM sleep disorders, hypersomnia, sleep-wake cycle disorders, narcolepsy and sleep disorders associated with shift work or irregular work schedules, nocturnal enuresis and restless-legs syndrome.
According to a first embodiment of an eleventh aspect of the present invention is provided a process for the preparation of a compound of Formula (d) 
by reacting a compound of formula (b) 
with a compound of formula (c) 
in the presence of ethyl diazoacetate and toluene, wherein R4 is cyano, halo, nitro or C1-3perfluoroalkyl and X is p-toluenesulfonyl, benzenesulfonyl, methansulfonyl or trifluoromethanesulfonyl.
According to another embodiment of the eleventh aspect of the present invention is provided a process for the preparation of a compound of Formula (d1) 
by reacting a compound of formula (b) 
with a compound of formula (c) 
in the presence of tert-butyl diazoacetate and toluene, wherein R4 is cyano, halo, nitro or C1-3perfluoroalkyl and X is p-toluenesulfonyl, benzenesulfonyl, methansulfonyl or trifluoromethanesulfonyl.
According to a twelvth aspect of the present invention is provided a method of treating sexual dysfunction in a mammal in need thereof comprising the administration of a pharmaceutically acceptable salt or solvate of a compound of Formula (I) and a compound selected from the group of known erectile dysfunction agents including sildenafil.
Other embodiments of the present invention may comprise suitable combinations of two or more of the embodiments and/or aspects disclosed herein.
Yet other embodiments and aspects of the invention will be apparent according to the description provided below.